Abstract
N-methyl-D-aspartate receptors (NMDARs) respond to glutamate to allow the influx of calcium ions and the signaling to the mitogen-activated protein kinase (MAPK) cascade. Both MAPK- and Ca2+-mediated events are important for both neurotransmission and neural cell function and fate. Using a heterologous expression system, we demonstrate that NMDAR may interact with the EF-hand calcium-binding proteins calmodulin, calneuron-1, and NCS1 but not with caldendrin. NMDARs were present in primary cultures of both neurons and microglia from cortex and hippocampus. Calmodulin in microglia, and calmodulin and NCS1 in neurons, are necessary for NMDA-induced MAP kinase pathway activation. Remarkably, signaling to the MAP kinase pathway was blunted in primary cultures of cortical and hippocampal neurons and microglia from wild-type animals by proteins involved in neurodegenerative diseases: α-synuclein, Tau, and p-Tau. A similar blockade by pathogenic proteins was found using samples from the APPSw,Ind transgenic Alzheimer’s disease model. Interestingly, a very marked increase in NMDAR–NCS1 complexes was identified in neurons and a marked increase of both NMDAR–NCS1 and NMDAR–CaM complexes was identified in microglia from the transgenic mice. The results show that α-synuclein, Tau, and p-Tau disrupt the signaling of NMDAR to the MAPK pathway and that calcium sensors are important for NMDAR function both in neurons and microglia. Finally, it should be noted that the expression of receptor–calcium sensor complexes, specially those involving NCS1, is altered in neural cells from APPSw,Ind mouse embryos/pups.
Highlights
As longevity increases, neurodegenerative diseases such as Alzheimer’s (AD) and Parkinson’s (PD) diseases become a challenge for health and social security systems
Previous data suggest an interaction of N-methyl-D-aspartate receptor (NMDAR) and CaM (Ehlers et al, 1996) that was here confirmed by means of bioluminescence resonance energy transfer (BRET) assays in a heterologous expression system where GluN1 fused to Rluc and the GluN2B were co-expressed for proper NMDA receptor reconstitution and functional activity (Figure 1)
BRET results confirmed that NMDAR may interact with NCS1 and calneuron-1 but not with caldendrin
Summary
Neurodegenerative diseases such as Alzheimer’s (AD) and Parkinson’s (PD) diseases become a challenge for health and social security systems. There is an urgent need for interventions that either prevent neurodegeneration or delay disease progression. The situation in the case of AD is worse; the current anti-AD drugs, acetylcholinesterase inhibitors, and N-methyl-D-aspartate receptor (NMDAR) modulators are of little anti-symptomatic efficacy and do not prevent disease progression (Gauthier et al, 2016; Szeto and Lewis, 2016). The NMDAR is one of the most important mediators of excitatory neurotransmission in the brain. It is a tetrameric protein complex formed by two GluN1 and a combination of one or two GluN2A or GluN2B subunits. Receptor subunit expression varies in different brain regions and they convey slightly different neural responses. A decrease in NMDAR expression and a variation in subunit composition has been reported in senescence and in AD animal models (Ułas and Cotman, 1997; Wakabayashi et al, 1999; Mishizen-Eberz et al, 2004)
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